Development of Penicillin-Based Carbonic Anhydrase Inhibitors Targeting Multidrug-Resistant Neisseria gonorrhoeae

被引：3

作者：

Bonardi, Alessandro ^{[1
,2
]}

Nocentini, Alessio ^{[1
,2
]}

Giovannuzzi, Simone ^{[1
,2
]}

Paoletti, Niccolo ^{[1
,2
]}

Ammara, Andrea ^{[1
,2
]}

Bua, Silvia ^{[3
]}

Abutaleb, Nader S. ^{[4
]}

Abdelsattar, Abdallah S. ^{[4
]}

Capasso, Clemente ^{[5
]}

Gratteri, Paola ^{[1
,2
]}

Flaherty, Daniel P. ^{[6
]}

Seleem, Mohamed N. ^{[4
,7
]}

Supuran, Claudiu T. ^{[1
,2
]}

机构：

[1] Univ Florence, NEUROFARBA Dept, Pharmaceut & Nutraceut Sect, I-50019 Florence, Italy

[2] Univ Florence, Lab Mol Modeling Cheminformat & QSAR, I-50019 Florence, Italy

[3] Univ Bucharest ICUB, Res Inst, Bucharest 050663, Romania

[4] Virginia Polytech Inst & State Univ, Dept Biomed Sci & Pathobiol, Virginia Maryland Coll Vet Med, Blacksburg, VA 24061 USA

[5] CNR, Ist Biosci & Biorisorse, I-80131 Naples, Italy

[6] Purdue Univ, Coll Pharm, Borch Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA

[7] Virginia Polytech Inst & State Univ, Ctr One Hlth Res, Blacksburg, VA 24061 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 11期

基金：

美国国家卫生研究院;

关键词：

HELICOBACTER-PYLORI; VIBRIO-CHOLERAE; FORCE-FIELD; ALPHA; PROTEINS;

D O I：

10.1021/acs.jmedchem.4c00740

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The development of antibacterial drugs with new mechanisms of action is crucial in combating the rise of antibiotic-resistant infections. Bacterial carbonic anhydrases (CAs, EC 4.2.1.1) have been validated as promising antibacterial targets against pathogens such as Helicobacter pylori, Neisseria gonorrhoeae, and vancomycin-resistant enterococci. A multitarget strategy is proposed to design penicillin-based CA inhibitor hybrids for tackling resistance by targeting multiple bacterial pathways, thereby resensitizing drug-resistant strains to clinical antibiotics. The sulfonamide derivatives potently inhibited the CAs from N. gonorrhoeae and Escherichia coli with K-I values in the range of 7.1-617.2 nM. Computational simulations with the main penicillin-binding protein (PBP) of N. gonorrhoeae indicated that these hybrid derivatives maintained the mechanism of action of the lead beta-lactams. A subset of derivatives showed potent PBP-related antigonococcal effects against multidrug-resistant N. gonorrhoeae strains, with several compounds significantly outperforming both the lead beta-lactam and CA inhibitor drugs (MIC values in the range 0.25 to 0.5 mu g/mL).

引用

页码：9613 / 9627

页数：15

共 55 条

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